Abstract 5765: Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers
Authors: Xiaofeng Chen, Jiaohui Pang, Cuicui Liu, Sha Wang, Yang Shao
Journal: Cancer Research (2022)

Abstract Background: Biliary tract carcinoma (BTC) is a relatively rare cancer worldwide and accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Genetic landscape of BTC can offer a comprehensive understanding of its carcinogenesis and clinical associations. The present study aims to compare the molecular features between BTC subtypes and explore clues for treatment therapies. Methods: We analyzed 258 BTC tissue samples including 70 GBCs and 188 CCAs with targeted sequencing (NGS) using a 425 caner-relevant genes panel. We identified the somatic alterations and MSI status of all samples. TMB was counted by summing all base substitutions and indels in the coding region of targeted genes. TMB-high (TMB-H) was defined as mutation number ≥ 10mut/Mb. Results: The most frequently mutated genes in 258 BTCs were TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%) and MCL1 (14.3%). Four gene mutations and 2 gene amplifications were significantly enriched in GBC compared to CCA (mutations P&amp;lt;0.05, amplifications P&amp;lt;0.01): TP53 (78.8% vs 47.9%), ARID2 (15.7% vs 3.7%), STK11 (12.9% vs 4.3%), TERT (24.3% vs 11.2%), CCNE1 and SOX2 amplifications (21.4% vs 2.7%, 4.3% vs 0%). However, ARID1A mutation (15.4% vs 5.7%), PBRM1 mutation (10.1% vs 0%), and MCL1 amplification (17.0% vs 5.7%) were more frequently existed in CAA (all P&amp;lt;0.05). Seven actionable alterations, including IDH1/2 (5.4%), FGFR1-4 (4.7%), ERBB2 (6.2%), PIK3CA (5.4%), MET (3.5%), and BRCA1/2 (5.0%), were detected with different occurrence frequencies in two subtypes. ERBB2 was predominant in GBC (15.7% vs 7.4%, p&amp;lt;0.001), while IDH1/2 and KRAS alteration rates were much higher in CCA (8% vs 0%, 31.4% vs 18.6%, both P&amp;lt;0.05). FGFR3 alterations were also tended to be enriched in CCA (7.1% vs 2.7%), although no significant difference was found. In general, there were 25.7% of GBC patients harboring actionable alterations versus 29.3% of CCA patients. In addition, 40 (15.5%, 13 GBCs and 27 CCAs) and 11 (4.3%, 10 GBCs and 1 CCA) patients were TMB-H and MSI-H, respectively, suggesting the possibility of benefit from immunotherapy. Conclusions: There were distinct molecular features in somatic variations and actionable alterations between GBSs and CCAs. In general, 44.3% of GBC and 46.3% CCA may benefit from targeted therapy and immunotherapy. This study could be helpful to establish treatment therapies for BTCs according to genetic information. Citation Format: Xiaofeng Chen, Jiaohui Pang, Cuicui Liu, Sha Wang, Yang Shao. Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5765.